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CHICAGO - Children with juvenile arthritis who are treated early and aggressively have better outcomes, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Chicago.

Many studies have shown that early and aggressive treatment is highly beneficial to adults with rheumatoid arthritis, but few studies have focused on this in children. About one child in every 1,000 develops some type of juvenile arthritis. These disorders can affect children at any age, although rarely in the first six months of life. It is estimated that around 300,000 children in the U.S. have been diagnosed with JIA. There are several types of JIA, all involving chronic (long-term) joint inflammation. Polyarticular JIA affects five or more joints and can begin at any age. Children diagnosed with polyarticular JIA in their teens may actually have the adult form of rheumatoid arthritis at an earlier-than-usual age.

Researchers recently looked at children with polyarticular JIA to see if early and aggressive treatment could get rid of their clinical signs of juvenile arthritis within six months and cause them to go into clinical remission within a year. In addition to this ambitious goal, the researchers — led by Carol Wallace, MD; professor of pediatrics, Children’s Hospital and Regional Medical Center, Seattle, Wash. — also looked at other signs of disease activity (such as a physician’s assessment of disease activity, a parent’s assessment of well-being, number of joints with arthritis, and number of joints with limited motion) to determine if any positive changes could be made.

“This is the first randomized, double blind clinical trial using inactive disease and remission as the main outcomes,” says Dr. Wallace. “It is not enough for treatments to improve JIA, we need to treat for remission of disease.”

The study included eighty-five children — ages two through 16 (predominately girls with an average age of 11) — who had been diagnosed with JIA, on average, five months before their participation. Each participant was randomly placed into one of two groups: the first group was placed on methotrexate by injection weekly, etanercept (Enbrel®), and prednisone (the prednisone was tapered to zero by four months) - this was called the M-E-P arm. The second group was placed on methotrexate (the same amount by injection) and two placebos (to imitate the etanercept and prednisone) - this group was called the MTX arm. The patients, their parents, and the researchers did not know which treatment individual patients were receiving.

Dr. Wallace’s team looked at the effectiveness and safety of treatment in both groups. Each group received follow up for up to 12 months. After four months of treatment, participants who improved by 70 percent continued on their blinded medications. Those who didn’t show 70 percent clinical improvement received unblinded etanercept and prednisone in addition to their methotrexate.

At six months of treatment, those patients who achieved clinical inactive disease (no disease activity at all) continued on their treatment until 12 months. Those who did not achieve clinical inactive disease were treated with unblinded etanercept and prednisone in addition to the methotrexate until the end of the study at 12 months.

At four months, 71 percent of patients in the M-E-P arm achieved 70 percent improvement compared to 44 percent of patients in the MTX arm, and Dr. Wallace says this is statistically significant. At six months, 40 percent of patients in the M-E-P arm achieved clinical inactive disease, compared to 23 percent in the MTX arm. “While this difference in achievement of clinical inactive diseases between the two treatment arms is not statistically significant, nearly one-third of patients overall achieved clinical inactive disease by six months of therapy, which is a remarkable result,” explains Dr. Wallace.

Analysis of all of the different patient variables revealed that the only one that predicted clinically inactive disease at six months was the disease duration at the beginning of the study. For each month earlier that treatment was started after onset of symptoms, the odds of clinically inactive disease increased by 30 percent, and — according to Dr. Wallace — this is highly significant and consistent with findings for rheumatoid arthritis.

By 12 months, 21 percent of participants from the M-E-P arm achieved clinical remission on medications compared to seven percent from the MTX arm.  “While the rate of achieving inactive disease and clinical remission on medication were not as high as we had hoped they were still very substantial and remarkable” says Dr. Wallace. “This study sets new standards for treatment, response and outcomes for children with polyarticular JIA. Achieving a 70 percent improvement by four months and inactive disease by six months are achievable goals. One of the most remarkable findings of the study was the importance of early treatment. There does appear to be a window of opportunity for JIA as there is for RA.”

In addition, the researchers noted that there were no differences in safety between the two groups. Side effects — including infections — were similar within the two groups. There were three serious side effects throughout the duration of the study: pneumonia, psychosis, and bacteria in the blood with septic arthritis. All of these resolved.

“This is a remarkable study that demonstrates the importance of early, aggressive therapy for children with polyarticular JIA,” says Dr. Wallace. “Our patients deserve the best, most effective therapy.”

The American College of Rheumatology is an international professional medical society that represents more than 8,000 rheumatologists and rheumatology health professionals around the world. Its mission is to advance rheumatology. The ACR/ARHP Annual Scientific Meeting is the premier meeting in rheumatology. For more information about the meeting, visit Follow the meeting on Twitter by using the official hashtag: #ACR2011.

Editor’s Notes: Carol Wallace, MD will present this research during the ACR Annual Scientific Meeting at McCormick Place Convention Center at Noon on Sunday, November 6 in Room W375d. Dr. Wallace will be available for media questions and briefing at 1:30 pm on Monday, November 7 in the on-site press conference room, W 175C.

Learn more about living well with rheumatic disease as well as rheumatologists and the role they play in health care. Also, discover the ACR’s Simple Tasks campaign, which highlights the severity of rheumatic diseases and the importance of early and appropriate referral to a rheumatologist

Presentation Number: 721

Trial of Early Aggressive Therapy in Polyarticular Juvenile Idiopathic Arthritis

Carol Wallace (Childrens Hosp & Regional Med, Seattle, WA)
Edward H. Giannini (PRCSG-Cincinnati Children's Hospital Medical Center, Cincinnati, OH)
Steven J. Spalding (Cleveland Clinic, Cleveland, OH)
Philip Hashkes (Shaare Zedek Medical Center, Tel Aviv, Israel)
Kathleen M. O'Neil (Okla Univ Health Science Ctr, Oklahoma City, OK)
Andrew S. Zeft (Cleveland Clinic, Cleveland, OH)
Ilona S. Szer (Rady Childrens Hosp San Diego, San Diego, CA)
Sarah Ringold (Children's Hosp Regional Med, Seattle, WA)
Hermine Brunner (Cincinnati Children's Hospital Medical Center, Cincinnati, OH)
Laura E. Schanberg (Duke University Medical Center, Durham, NC)
Robert P. Sundel (Childrens Hosp Medical Center, Boston, MA)
Diana Milojevic (UCSF, San Francisco, CA)
Marilynn G. Punaro (Texas Scottish Rite Hospital, Dallas, TX)
Peter Chira (Stanford University, Palo Alto, CA)
Beth S. Gottlieb (Schneider Children's Hospital, New Hyde Park, NY)
Gloria Higgins (PRCSG, Columbus, OH)
Norman T. Ilowite (Children's Hospital Montefiore, Bronx, NY)
Yukiko Kimura (Hackensack Univ Medical Ctr, Hackensack, NJ)
Anne Johnson (Cincinnati Child Hosp Med Ctr, Cincinnati, OH)
Stephanie Hamilton (Childrens Hosp & Regional Med, Seattle, WA)
Bin Huang (Cincinnati Children's Hospital Medical Center, Cincinnati, OH)
Daniel J. Lovell (Cincinnati Children's Hospital Medical Center, Cincinnati, OH)

Early aggressive therapy produces superior outcomes in adults with RA, but evidence for a similar benefit has not been demonstrated in children with JIA.

Method:  The objectives of this study (abbrev TREAT) were to determine if aggressive treatment initiated early in the course of RF (+) or (-) polyarticular JIA (poly JIA) can induce clinical inactive disease (CID) within 6 mos (primary endpoint) and clinical remission on medication (CRM: CID for 6 continuous mos on medication; exploratory endpoint) within 1 yr of starting therapy.  Other endpoints were changes in the ACR pediatric core variables.

TREAT was designed as a multi-center, prospective, double blind, randomized, placebo controlled trial in children aged 2-16 yrs with onset of poly JIA <12 mos in duration.  Subjects were randomized 1:1 into 1 of 2 aggressive treatment arms: (Arm 1) MTX 0.5 mg/kg/wk SQ (40 mg max), plus etanercept (ETN) 0.8 mg/kg/wk (50 mg max), plus prednisolone (pred) 0.5 mg/kg/d (60 mg max) tapered to 0 by 17 wks or; (Arm 2) MTX (same dose as Arm 1) plus ETN placebo, plus pred placebo, then followed on protocol for up to 12 mos.  After 4 mos on therapy subjects who failed to achieve at least an ACR Pediatric 70 received open label ETN, MTX, and pred in the same doses as Arm 1.  At 6 mos, subjects who did not achieve CID received open label medication.  Efficacy analyses focused on the intent-to-treat approach.  Safety data were recorded for all subjects.

Result:  15 centers enrolled 85 subjects (64 [75%] female; median age 11.1 yrs; disease duration 4.1 mos).  69% were ANA+ and 36% were RF(+).  Median values at baseline of ACR pediatric core variables were: physician’s global assessment of disease activity 7.5; parent global assessment of well-being 5.5; ESR 33; number of joints with arthritis 19; number of joints with limited motion 11.5, C-HAQ 1.1.

At 4 mos, 30 of 42 (71%) subjects in Arm 1 and 19 of 43 (44%) in Arm 2 achieved an ACR Pediatric 70 (X2 = 6.5; p=0.011).  At 6 mos, 17 of 42 (40%) of subjects in Arm 1 achieved CID, compared to 10 of 43 (23%) in Arm 2 (X2 = 2.91; p = 0.088).  Logistic regression showed the only variable predictive of CID at 6 mos was disease duration at baseline.  The odds of CID increased by 1.324 times for each month earlier treatment was started after onset of symptoms (p=0.011).  Although all 6 ACR pediatric core variables showed highly significant improvement by 6 mos in both Arms (all p values <0.001), 5 showed statistically greater improvement in Arm 1 vs. Arm 2.  By 12 mos, 12 (14%) subjects achieved CRM; 9 (21%) had remained in Arm 1, and 3 (6%) had remained in Arm 2 throughout the study (p=0.053). 

There were no significant inter-arm differences in the incidence of Grade 3 or higher adverse events, including infections requiring systemic therapy.  There were 3 SAEs: pneumonia (Arm 1), psychosis (open label), and bacteremia with septic arthritis (open label).  All resolved without sequelae.

Conclusion: Although this trial did not reach its primary endpoint, early aggressive therapy in this cohort of children with severe JIA and a high rate of RF positivity resulted in substantial proportions of subjects achieving an ACR Pediatric 70 at 4 mos, CID at 6 mos, and CRM within 12 mos of treatment initiation.

Disclosure: C. Wallace, Amgen, 2, Pfizer Inc, 2, Bristol myers Squibb, 5 ; E. H. Giannini, None; S. J. Spalding, None; P. Hashkes, None; K. M. O'Neil, None; A. S. Zeft, None; I. S. Szer, None; S. Ringold, None; H. Brunner, None; L. E. Schanberg, Pfizer Inc, 2 ; R. P. Sundel, None; D. Milojevic, None; M. G. Punaro, None; P. Chira, None; B. S. Gottlieb, None; G. Higgins, None; N. T. Ilowite, Abbott Immunology Pharmaceuticals, 8, Genentech and Biogen IDEC Inc., 8, Regeneron, 2, Novartis Pharmaceutical Corporation, 5, Centocor, Inc., 5 ; Y. Kimura, Genentech and Biogen IDEC Inc., 5 ; A. Johnson, None; S. Hamilton, None; B. Huang, None; D. J. Lovell, Abbott Immunology Pharmaceuticals, 5, Bristol-Myers Squibb, 5, Centocor, Inc., 5, Hoffmann-La Roche, Inc., 5, UBC, 5 .

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